Characteristics and long-term mortality of patients with non-MAFLD hepatic steatosis

Background & Aims A cluster of hepatic steatosis without metabolic abnormalities has been excluded by the MAFLD definition, referred to as non-MAFLD steatosis. We aimed to characterize the non-MAFLD steatosis. Methods We included 16,308 individuals from the UK Biobank who had magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) to describe the clinical and genetic features of non-MAFLD steatosis in a cross-sectional design, and 14,797 individuals of the NHANES III who underwent abdominal ultrasonography at baseline to assess the long-term mortality of non-MAFLD steatosis in a prospective cohort design. Results Of 16,308 individuals in the UK Biobank, 2747 fatty liver disease (FLD) cases (2604 MAFLD and 143 non-MAFLD) and 3007 healthy controls (without metabolic dysfunctions) were identified. The mean PDFF (10.65 vs . 9.00) and the proportion of advanced fibrosis (fibrosis-4 index > 2.67, 1.27% vs. 1.40%) were comparable between MAFLD and non-MAFLD steatosis. Non-MAFLD steatosis has the highest minor allele frequency of PNPLA3 rs738409, TM6SF2 rs58542926, and GCKR rs1260326 in contrast to the other two groups. The genetic risk score calculated by PNPLA3 , TM6SF2 , and GCKR has a certain predictive ability for non-MAFLD steatosis (AUROC = 0.69). NHANES III population showed that compared to healthy individuals, the adjusted hazard ratio of non-MAFLD steatosis increased by 1.52 (95% confidence interval: 1.21–1.91) and 1.78 (95% confidence interval: 1.03–3.07) for all-cause and heart disease-related mortality, respectively. Conclusions Non-MAFLD steatosis has comparable degrees of hepatic steatosis and fibrosis to MAFLD and increases the risk of mortality. Genetic predisposition highly contributes to the risk of non-MAFLD steatosis.